The rise in the incidence and prevalence of food allergy has been attributed to a confluence of environmental factors brought about by a modern life style, including altered gut microbiota, acting upon genetically susceptible individuals. Central to the development of food allergy is the breakdown of oral tolerance, normally maintained by food allergen-specific T regulatory (TR) cells. However, the mechanisms by which oral tolerance is disrupted remain obscure. By employing a novel genetic murine model of human food allergy involving a gain of function mutation in the IL-4 receptor alpha chain immunotyrosine inhibitory motif (ITIM), we could demonstrate that food allergy is associated with reduced formation of allergen-specific induced TR (iTR) cells. Those that are generated are dysfunctional, failing to prevent sensitization or to suppress active disease. This failure is relaed to their reprogramming into Th2-like cells, a phenomenon that is also observed in TR cells of human food allergic subjects. Abrogation TR cell Th2 reprogramming by TR cell-specific STAT6 deficiency restores the capacity of allergen-specific Il4raF709 TR cells to suppress disease. Food allergic Il4raF709 mice manifest dysregulation of gastrointestinal innate immune pathways, including innate lymphoid cells 2 (ILC2s) and conventional dendritic cells. They also exhibit dysbiotic commensal flora that are pathogenic, evidenced by their promotion of food allergy when transferred into germ-free (GF) mice. Reciprocally, flora of food allergy- tolerant mice prevented disease induction when transplanted into GF Il4raF709 mice. Importantly, Il4raF709 mice exhibited heightened IgA and IgE anti-commensal antibody responses, consistent with an augmented adaptive immune response to gut microbiota. Accordingly, we propose that excessive IL-4R signaling in TR cells in the context of skewed Th2 environment in the gut is a key pathogenic mechanism by which breakdown oral tolerance takes place, resulting in the suppression of allergen-specific TR cell generation and the reprogramming of those cells formed into pathogenic Th2-like cells. We will also propose that a dysregulated, Th2 promoting innate immune response plays a critical role in amplifying disease. Finally, we hypothesize that discrete dysbiotic bacterial communities play a critical pathogenic role in food allergy by eliciting an augmented adaptive immune response to component bacteria, which in turn potentiates sensitization to food allergens. Our proposed studies will identify fundamental mechanisms by which oral tolerance is subverted in food allergy, and will directly impact the development of curative therapies.